The Janus kinase (JAK) inhibitor ruxolitinib is the only U.S. Food and Drug Administration–approved therapy for myelofibrosis (MF), but the resultant hematologic adverse events (AEs) can lead to dose reductions or interruptions.

In the SIMPLIFY-1 trial, Ruben A. Mesa, MD, director of the UT Health San Antonio Cancer Center in Texas, and co-authors evaluated momelotinib, an oral, small-molecule JAK1/2 inhibitor, as an alternative to ruxolitinib. Their results, published in the Journal of Clinical Oncology, were mixed: The investigational agent was non-inferior to ruxolitinib for spleen volume reduction, but ruxolitinib was superior in reducing symptom burden.

Patients were excluded if they had spleen irradiation within three months prior to study treatment, certain cancers, or uncontrolled concurrent illness.

Participants were stratified based on transfusion dependence (yes or no; defined as ≥4 units of red blood cells [RBCs] or hemoglobin <8 g/dL in the prior 8 weeks) and platelet count (<100×109/L, ≥100×109/L and ≤200×109/L, and >200×109/L), then randomized 1:1 to receive:

Treatment discontinuation appeared to be more common in the momelotinib group (18.6%) than the ruxolitinib group (7.4%; p value not reported), and a total of 376 patients completed the 24-week phase: 175 in the momelotinib group and 201 patients in the ruxolitinib group.

The primary endpoint (spleen volume reduction ≥35% from baseline at week 24) was evaluable in 184 momelotinib-treated patients and 204 ruxolitinib-treated patients. A similar number of patients in each treatment group achieved the primary endpoint (n=57 [26.5%] vs. 63 [29.0%]), for a non-inferiority proportion difference of 0.09, making momelotinib non-inferior to ruxolitinib (p=0.01).

Ruxolitinib was better than momelotinib in reducing symptoms (secondary endpoint; defined as total symptom score [TSS] reduction >50% reduction from baseline). Of the 190 and 175 patients, respectively, available for TSS assessment, more ruxolitinib-treated patients met this endpoint (n=89 [42.2%] vs. 60 [28.4%]; n=60), and non-inferiority for momelotinib was not met (p=0.98).

However, transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib:

The most common, any-grade treatment-related AEs in the momelotinib and ruxolitinib cohorts are reported in the TABLE.

Grade ≥3 AEs were reported by 35.5 percent of momelotinib-treated patients and 43.5 percent of ruxolitinib-treated patients. The most common grade ≥3 AEs in the momelotinib group were thrombocytopenia (7.0%), anemia (5.6%), diarrhea (2.8%), hypertension (2.8%), and neutropenia (2.8%), while the most common in the ruxolitinib group were anemia (23.1%), neutropenia (4.6%), thrombocytopenia (4.6%), and hypertension (4.2%). Serious AEs occurred in 22.9 percent and 18.1 percent of patients, respectively.

Treatment discontinuation occurred more frequently in the momelotinib group (13.1% vs. 5.6%; p value not reported), and seven deaths were reported in each cohort.

“Results were mixed and indicate that although momelotinib may offer less symptom control than ruxolitinib, there is a comparable spleen response and a potential benefit in terms of anemia,” the authors concluded.

The study is limited by its 24-week follow-up period. Long-term efficacy and safety evaluations are warranted, according to the authors.

Gilead supported the study.

The corresponding authors report financial support from Gilead, the manufacturer of momelotinib, and Incyte, the manufacturer of ruxolitinib. Impact Communications provided editorial support.